Abstract In previous studies we have demonstrated that CTHRC1 (Collagen Triple Helix Repeat Containing 1), a factor discovered in our laboratory, is constitutively expressed only in brain and bone and not in other tissues during adulthood. However, CTHRC1 is highly expressed in activated fibroblasts and interstitial cells of tissues undergoing remodeling and repair. We discovered that CTHRC1 is a circulating factor but only approximately 30% of healthy human subjects have detectable levels of CTHRC1 in plasma, ranging in concentration from low pg/ml to almost 100ng/ml. Similar to most humans, circulating levels of CTHRC1 are not detectable in mice and rats and forced transgenic overexpression of CTHRC1 under Pdgfrb promoter control does also not result in detectable CTHRC1 plasma levels. Thus there are two pools of CTHRC1; one that is generated locally in tissues undergoing repair requiring >48 hours to be available, and a second pool of circulating CTHRC1 available at all times and found only in a minority of human subjects. The significance of circulating CTHRC1 for the cardiovascular system became apparent when we obtained plasma samples from patients experiencing cardiac arrest, a condition with approximately 50% mortality. High CTHRC1 levels (?0.75ng/ml) are associated with substantially higher survival rates in humans experiencing cardiac arrest. While CTHRC1 is not expressed in the adult heart, it is highly induced in fibroblasts activated in response to myocardial infarction. To test the role of CTHRC1 in acute ischemic injury, we performed coronary artery ligation in Cthrc1 null mice and Cthrc1 transgenic mice on the Cthrc1 null background with physiologically relevant CTHRC1 plasma levels in the ng/ml range found in humans. Strikingly, 70% of Cthrc1 null mice died 3-4 days after the ischemic injury whereas all transgenic mice survived. With the goal of identifying the mechanism for this dramatic finding we performed in vitro studies and found that CTHRC1 promotes cell survival in variety of cell types including endothelial cells. Complete metabolic monitoring revealed that Cthrc1 null mice have increased energy expenditure at rest and analysis of cell metabolism in vitro revealed that in the presence of CTHRC1 mitochondrial respiration is significantly increased whereas glycolysis is reduced, leading us to hypothesize that CTHRC1 functions as a mediator of metabolic efficiency. Overall, this proposal will test the hypothesis that CTHRC1 functions as a mediator of cell survival under conditions of cell stress by increasing metabolic efficiency, which in turn protects from the deadly consequences of acute ischemic injury. We will determine if increasing circulating- or CTHRC1 tissue levels provides cardiovascular protection by limiting the deleterious consequences of myocardial ischemia. Using genetic mouse models and in vitro approaches the underlying mechanism of action will be identified, and this will provide the foundation for novel therapeutic approaches to improve outcomes of acute ischemic conditions.